Dominant Myocardial Fibrosis and Complex Immune Microenvironment Jointly Shape the Pathogenesis of Arrhythmogenic Right Ventricular Cardiomyopathy

Abstract

BackgroundArrhythmogenic right ventricular cardiomyopathy (ARVC) is a heritable life-threatening myocardial disease characterized by ventricular arrhythmias and sudden cardiac death. Few studies used RNA-sequencing (RNA-seq) technology to analyze gene expression profiles, hub genes, dominant pathogenic processes, immune microenvironment in ARVC. This study aimed to explore these questions via integrated bioinformatics analysis.MethodsRNA-sequencing datasets of GSE107475, GSE107311, GSE107156, and GSE107125 were obtained from the Gene Expression Omnibus database, including right and left ventricular myocardium from ARVC patients and normal controls. Weighted gene co-expression network analysis identified the ARVC hub modules and genes. Functional enrichment and protein-protein interaction analysis were performed by Metascape and STRING. Single-sample gene-set enrichment analysis (ssGSEA) was applied to assess immune cell infiltration. Transcription regulator (TF) analysis was performed by TRRUST.ResultsThree ARVC hub modules with 25 hub genes were identified. Functional enrichment analysis of the hub genes indicated that myocardial fibrosis was the dominant pathogenic process. Higher myocardial fibrosis activity existed in ARVC than in normal controls. A complex immune microenvironment was discovered that type 2 T helper cell, type 1 T helper cell, regulatory T cell, plasmacytoid dendritic cell, neutrophil, mast cell, central memory CD4 T cell, macrophage, CD56dim natural killer cell, myeloid-derived suppressor cell, memory B cell, natural killer T cell, and activated CD8 T cell were highly infiltrated in ARVC myocardium. The immune-related hub module was enriched in immune processes and inflammatory disease pathways, with hub genes including CD74, HLA-DRA, ITGAM, CTSS, CYBB, and IRF8. A positive linear correlation existed between immune cell infiltration and fibrosis activity in ARVC. NFKB1 and RELA were the shared TFs of ARVC hub genes and immune-related hub module genes, indicating the critical role of NFκB signaling in both mechanisms. Finally, the potential lncRNA–miRNA–mRNA interaction network for ARVC hub genes was constructed.ConclusionMyocardial fibrosis is the dominant pathogenic process in end-stage ARVC patients. A complex immune microenvironment exists in the diseased myocardium of ARVC, in which T cell subsets are the primary category. A tight relationship exists between myocardial fibrosis activity and immune cell infiltration. NFκB signaling pathway possibly contributes to both mechanisms.

Evaluation of Nandrolone Decanoate Effects on Sinoatrial Node in Experimental Rat Model (Histological and Immunohistochemical study)

“…It was stated that the increase of intrafasicular connective tissue usually represent a response to a loss of cardiomyocytes where fibroblasts replace the damaged area, with subsequent formation of collagen fibers [31] . Furthermore, Lu et al [32] reported a positive linear correlation between myocardial fibrosis activity and immune cell infiltration.…”

The role of CD74 in cardiovascular disease

“…The potential underlying mechanism is related to expression of ATPase, NCX, ryanodine receptor 2 (RyR2) phosphorylation and CaMKII-RyR2 signaling activation triggered by MIF, which can be attenuated by blocking CD74 ( Figure 5 ) ( 93 ). In additional, bioinformatic analysis of the myocardium of patients with arrhythmogenic right ventricular cardiomyopathy (ARVC) versus normal controls revealed an immune-related hub module, which Protein-Protein Interaction Network analysis identified CD74 as one of the most important hub genes ( 94 ). This information suggests that MIF/CD74 signaling is a potential therapeutic intervention for arrhythmia.…”